Huntington's disease (HD) is a neurodegenerative disease caused by the genetic mutation resulting in expression of a mutant form of the Huntington (HTT) protein that causes inexorable central nervous system deterioration with loss of brain tissue, abnormal physical movements, cognitive impairment, and psychiatric symptoms. HD is a fatal, progressive disorder with no known effective disease-modifying treatment. The development of effective treatments for HD will be greatly accelerated by a validated assay that can sensitively measure small changes in pathology of HD. Biomarkers are measurable factors that are associated with the illness and when effective, can serve as surrogates for disease diagnosis, severity, and/or progression. Biomarkers can be more sensitive and reflective of disease pathology than clinical symptoms, which may take years to become apparent. For example, a useful biomarker can reflect the target engagement of a drug and help establish the dose and dosing frequency requirements long before any change in clinical symptoms occurs. To date, no such sensitive and validated biomarkers are available for HD. This proposal will evaluate the ability of a new biomarker to reflect HD pathology, predict its course and allow for quantitative assessment of target engagement in clinical trials. This biomarker is CSF-enhanced-aggregation, a quantitative measure of Htt aggregation in HD cell models following the external application of CSF from HD patients. Abnormal aggregation of Htt protein is a key feature of HD pathology. The recently developed CSF-enhanced-aggregation assay that this proposal will refine and validate is predicted to be sensitive to HD progression etiopathology. This proposal will utilize CSF samples collected from subjects in the PREDICT-HD naturalistic study of gene-positive and gene-negative individuals. We will establish the sensitivity and specificity of this CSF biomarker and its relationship to onset of diagnosis and ability to monitor the progression of HD.